Extracellular matrix proteins and chemoradiotherapy: α5β1 integrin as a predictive marker in rectal cancer

Jayne, David; Heath, Rebecca; Dewhurst, O; Scott, Nigel; Guillou, Pierre-José

doi:10.1053/ejso.2001.1182

Cited by 29 publications

(28 citation statements)

References 30 publications

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“…Studies of vascular basement membrane in human tumors illustrate that the limited extent of collagen positivity in our preclinical models are relevant to that seen clinically. For example, tumors from 27 of 32 patients with rectal cancer demonstrated little to no staining for collagen expression (45). Similarly, in glioblastomas and pilocytic astrocytomas, collagen content was ~3% (range ~1–8%) of the tumor area (46).…”

Section: Discussionmentioning

confidence: 99%

Tumor Vascular Microenvironment Determines Responsiveness to Photodynamic Therapy

et al. 2012

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The efficacy of photodynamic therapy (PDT) depends upon the delivery of both photosensitizing drug and oxygen. In this study, we hypothesized that local vascular microenvironment is a determinant of tumor response to PDT. Tumor vascularization and its basement membrane (collagen) were studied as a function of supplementation with basement membrane matrix (Matrigel) at the time of tumor cell inoculation. Effects on vascular composition with consequences to tumor hypoxia, photosensitizer uptake and PDT response were measured. Matrigel-supplemented tumors developed more normalized vasculature, composed of smaller and more uniformly-spaced blood vessels than their unsupplemented counterparts, but these changes did not affect tumor oxygenation or PDT-mediated direct cytotoxicity. However, PDT-induced vascular damage increased in Matrigel-supplemented tumors, following an affinity of the photosensitizer Photofrin for collagen-containing vascular basement membrane coupled with increased collagen content in these tumors. The more highly-collagenated tumors demonstrated more vascular congestion and ischemia after PDT, along with a higher probability of curative outcome that was collagen dependent. In the presence of photosensitizer-collagen localization, PDT effects on collagen were evidenced by a decrease in its association with vessels. Together, our findings demonstrate that photosensitizer localization to collagen increases vascular damage and improves treatment efficacy in tumors with greater collagen content. The vascular basement membrane is thus identified to be a determinant of therapeutic outcome in PDT of tumors.

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Section: Discussionmentioning

confidence: 99%

Tumor Vascular Microenvironment Determines Responsiveness to Photodynamic Therapy

et al. 2012

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“…In a study of metastatic melanoma, longer disease free survival and overall survival correlated with β1 expression [16], while neuroblastoma aggressiveness was correlated with expression of integrin αvβ3 and αvβ5 by the microvascular endothelium [17]. Studies of acute lymphoblastic leukemia show that β2 expression was significantly associated with splenomegaly [18], and expression of α5β1 was associated with positive response to chemotherapy in patients with rectal cancer [19]. Finally, node negative nonsmall cell lung cancer patients whose tumors over-express integrin α5 had a lower survival rate than those whose did not [20].…”

Section: Integrins As Therapeutic Markersmentioning

confidence: 99%

The Promise of Integrins as Effective Targets for Anticancer Agents

Rust

Carper

Plopper

2002

BioMed Research International

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This review will briefly describe integrin function, address why integrins are attractive targets for chemotherapeutic drug design, and discuss some ongoing studies aimed at inhibiting integrin activity. Integrins are cell surface heterodimeric receptors. They modulate many cellular processes including: growth, death (apoptosis), adhesion, migration, and invasion by activating several signaling pathways. Many potential chemotherapeutic agents target integrins directly (eg, polypeptides, monoclonal antibodies, adenovirus vectors). These agents may be clinically useful in controlling the metastatic spread of cancer.

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“…Proliferating endothelial cells express several integrin molecules, which are not expressed on quiescent endothelial cells in normal tissue or blood vessels, like α 5 β 1 , α v β 3 , and α 4 β 1 (Aiyer and Varner, 2005. In particular, integrin α 5 β 1 is minimally expressed in normal vasculature but is significantly up-regulated in tumor vasculature and on tumor cells such as prostate, breast, colon and rectal cancer (Chen et al, 2004, Ellis, 2003, Gong et al, 1997, Jayne et al, 2002, Jia et al, 2004, Livant et al, 2000. Previous studies suggest that peptide and antibody antagonists of the integrin α 5 β 1 are potent inhibitors of tumor growth, tumor induced angiogenesis, and tumor metastasis (Jia et al, 2004, Livant et al, 2000, Meerovitch et al, 2003, Shannon et al, 2004, Stoeltzing et al, 2001, Stoeltzing et al, 2003, White et al, 2001, Yokoyama and Ramakrishnan, 2004.…”

Section: Introductionmentioning

confidence: 99%

Targeting Colon Cancer Cells Using PEGylated Liposomes Modified With a Fibronectin-Mimetic Peptide

Garg

Tisdale

Kokkoli

2009

Journal of Medical Devices

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Integrin α 5 β 1 is expressed on several types of cancer cells, including colon cancer, and plays an important role in tumor growth and metastasis. The ability to target the integrin α 5 β 1 using an appropriate drug delivery nano-vector can significantly help in inhibiting tumor growth, reducing tumor metastasis, and decreasing deleterious side effects associated with different cancer therapies. Liposomes are nano-sized phospholipid bilayer vesicles that have been extensively studied as drug delivery carriers. The goal of this study is to design stealth liposomes (liposomes covered with polyethylene glycol (PEG)) that will target colon cancer cells that express the integrin α 5 β 1 . The PEG provides a steric barrier allowing the liposomes to circulate in the blood and the functionalizing moiety, PR_b peptide, will specifically recognize and bind to α 5 β 1 expressing cells. PR_b is a novel peptide sequence that mimics the cell adhesion domain of fibronectin, and includes four building blocks, RGDSP (the primary recognition site for α 5 β 1 ), PHSRN (the synergy site for α 5 β 1 ), a (SG) 5 linker, and a KSS spacer. In this study we have demonstrated that by varying the amount of PEG (PEG750 or PEG2000) and PR_b on the liposomal interface we can engineer nano-vectors that bind to CT26.WT, HCT116, and RKOcolon cancer cells in a specific manner and are internalized through most likely α 5 β 1 -mediated endocytosis. GRGDSP-targeted stealth liposomes bind to colon cancer cells and internalize, but they have much lesser efficiency than PR_b-targeted stealth liposomes, and more importantly they are not as specific since many integrins bind to RGD peptides. PR_b-targeted stealth liposomes are as cytotoxic as free 5-Fluorouracil (5-FU) and exert the highest cytotoxicity on CT26.WT cells compared to GRGDSP-targeted stealth liposomes and non-targeted stealth liposomes. Thus, the proposed targeted delivery system has the great potential to deliver a therapeutic load directly to colon cancer cells, in an efficient and specific manner.

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Extracellular matrix proteins and chemoradiotherapy: α5β1 integrin as a predictive marker in rectal cancer

Cited by 29 publications

References 30 publications

Tumor Vascular Microenvironment Determines Responsiveness to Photodynamic Therapy

Tumor Vascular Microenvironment Determines Responsiveness to Photodynamic Therapy

The Promise of Integrins as Effective Targets for Anticancer Agents

Targeting Colon Cancer Cells Using PEGylated Liposomes Modified With a Fibronectin-Mimetic Peptide

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